Regiospecific synthesis of bicyclo- and heterobicyclo-gem-difluorocyclobutenes using functionalized fluoroallenes and a novel Mo-catalyzed intramolecular [2 + 2] cycloaddition reaction

Article abstract of DOI:10.1021/ja0263893

The first synthesis of functionalized gem-difluoroallenes 4 served as platform for an unprecedented molybdenum-catalyzed intramolecular allene-alkyne [2 + 2]-cycloaddition that produced 6, a hitherto unknown class of bicyclo- and heterobicyclo-CF₂

Full text of DOI:10.1021/ja0263893

Published on Web 05/17/2002
Regiospecific Synthesis of Bicyclo- and
Heterobicyclo-gem-difluorocyclobutenes Using Functionalized Fluoroallenes
and a Novel Mo-Catalyzed Intramolecular [2 + 2] Cycloaddition Reaction
Qilong Shen and Gerald B. Hammond*
Department of Chemistry and Biochemistry, UniVersity of Massachusetts Dartmouth,
North Dartmouth, Massachusetts 02747
Received April 1, 2002
It is well established that the replacement of a hydrogen atom
with fluorine in organic compounds brings about major biological
and chemical changes.1 Despite advances in fluorination strategies,2
the synthesis of alicyclic gem-difluoro compounds is approached
on a case-by-case basis.3 A broader synthetic strategysthe cy-
cloaddition of functionalized gem-difluoro-allenesspioneered by
Dolbier,4 has remained largely unexplored, hampered by the
difficulty in synthesizing such fluorinated intermediates. Indeed,
only few difluoroallenes R2CdCdCF2 (R ) H, Me, Ph, Bu) have
been reported,5 and even conjugated gem-difluorodienes are rare.6,7
Conceptually, a functionalized difluoroallene such as 4 (Scheme
1) could be prepared by appending an appropriate olefinic or alkynyl
fragment to allenylsilane 2. Allene 4 would be an ideal cyclization
partner for the generation of a diverse array of fluorocyclic
compounds. We now report the first synthesis of a functionalized
gem-difluoroallene 4 and its novel molybdenum-catalyzed intramo-
lecular allene-alkyne [2 + 2]-cycloaddition that produced 6, a
hitherto unknown class of CF2-containing fused cyclobutenes.
Pd-catalyzed alkylation methodology9 (4a-g in eq 1 and Table 1).
By exercising strict control on the reaction conditions we minimized
the formation of the isomeric dienes 3a-g. Surprisingly, the
alkylation reaction of 2b with malononitrile or ethyl cyanoacetate
yielded a larger ratio of 3/4. The oxygen in 2a could be substituted
with nitrogen using propargylic amines, under Mitsunobu’s condi-
tions10 (4h-j). In these cases, the corresponding diene isomer 3
was not found. Prior to our work, microwave spectroscopy and
theoretical calculations on the geometries of the parent 1,1-
difluoroallene showed that the CdC and C-F bond lengths would
decrease with increasing fluorine substitution and FCF bond angles
should resemble sp3 hybridization.11 Our X-ray data,12 obtained from
crystals of 4h-j, provided the first crystallographic support to the
above statements.
Scheme 1
Although, in theory, an intramolecular cycloaddition of 4c-j
could be used to prepare bicyclic fluorinated compounds, there are
but a handful reports detailing intramolecular metal-mediated allene
cycloadditions,13 none of which involved allene-alkyne [2 + 2]
cycloadditions. Equipped with an efficient synthesis of function-
alized gem-difluoroallenes 4, we attempted the Co-mediated Pau-
son-Khand reaction,14 and although we succeeded in isolating the
stable Co-alkyne complex, the subsequent [2 + 2 + 1] cycload-
dition did not occur. Use of ancillary agents such as NMO or DMSO
at various temperatures did not bring about the cyclization either.
We then decided to adopt Brummond’s conditions,15 using molyb-
denum to affect the cycloaddition (eq 2).
Our recently discovered difluoroallenyl indium 1 (Scheme 1)
reacted nucleophilically with aldehydes to yield the expected
homopropargylic alcohols, but in the presence of aqueous formal-
dehyde, it produced allenyl alcohol 2a.8 Conversion of the hydroxyl
2a into its corresponding halide 2b was achieved cleanly. Allene
2b isomerized to the themodynamically more stable conjugated
diene isomer under Pd-mediated cross-coupling conditionss
including Suzuki and Sonogashirasyielding gem-difluoro conju-
gated diene 3 in high yields.7 Similarly, displacement of bromide
in 2b with a phosphorus nucleophile produced the corresponding
1,3-dienylphosphonate 3h (R ) P(O)(OEt)2,) in what could be
formally construed as a SN2′ reaction. The homologation of the
side chain in 2b was achieved using soft nucleophiles and Trost’s
The intramolecular cyclization of 4 did not produce the Pauson-
Khand product but a novel fused cyclobutene 6,16 in 90% yield.
No traces of the [3.2.0] exocyclic difluoromethylene regioisomer
could be detected. TIPS cleavage of 4 using TBAF resulted in the
efficient formation of diyne 5.
* Corresponding author. E-mail: ghammond@umassd.edu. Telephone: 508-
999-8865. Fax: 508-910-6918.
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J. AM. CHEM. SOC. 2002, 124, 6534-6535
10.1021/ja0263893 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Functionalized Difluoroallene Derivatives
and Their Mo(CO)6-Catalyzed Intramolecular [2 + 2]
Cycloadditiona
rate of carbonylation. Moreover, since the electron-withdrawing
gem-difluoro substituent would be expected to favor both processes,
it is interesting that reductive elimination wins. We are currently
investigating this and other modes of metal-mediated cyclizations
using mono- and difluorinated allenes.
Acknowledgment. The financial support of the Petroleum
Research Fund (PRF no. 36602-AC1) is acknowledged with
gratitude. We are grateful to Drs. James A. Golen, Department of
Chemistry and Biochemistry (UMass Dartmouth), and A. Chandra-
sekaran (UMass Amherst) for supplying the crystallographic data;
and to Professor Kay Brummond (U. Pittsburgh) for helpful
comments on Mo-cycloadditions.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for the substrates and products (PDF).
X-ray crystal data for 4h-i and 6e-g (CIF). This material is available
free of charge via the Internet at htt://pubs.acs.org.
References
(1) Recent books include: Hiyama, T. Organofluorine Compounds. Chemistry
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1999; Vol. Vol. E10a.
(2) Leading references include: Soloshonok, V. A.; Ed. Enantiocontrolled
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(12) An ORTEP view of 4h.
a No products were detected without Mo(CO)6 or at a lower temperature
(80 °C). b Isolated yields. c The ratio of 4/3 is based on 19F NMR. d When
1.5 equiv Mo(CO)6 was used, the yield is 90%.
(13) Relevant references include: Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263-3283. Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996,
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The fact that this Mo-mediated [2 + 2]-intramolecular allene-
alkyne cycloaddition is an intriguing departure from the expected
Pauson-Khand reaction prompted us to probe the reaction further
(Table 1). In all cases, gem-difluorocyclobutenes 6a-g were
obtained in very good or excellent yield. Crystallographic data
obtained from crystals 6e-g helped to secure the identity of this
novel functionalized gem-difluoro bicyclo [4.2.0] system.17
This cycloaddition, initially performed with 1.5 equiv of
molybdenum was repeated using catalytic amounts of molybdenum
(10 mol %) with equal success. Mechanistically, this reaction
represents a “formal” [2 + 2] cycloaddition, with the molybdenum
metallocycle undergoing a reductive elimination, rather than a CO
insertion. This behavior has been observed for other metals but
not for molybdenum. As we never observed the P-K product, the
relative rate of reductive elimination must be much faster than the
(14) Ishizaki, M.; Suzuki, D.; Hoshino, O. J. Fluor. Chem. 2001, 111, 81-90.
(15) Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000, 122, 4915-
4920.
(16) Only the parent 3,3-difluorocyclobutene is known: Dolbier, W. R., Jr.;
Al-Fekri, D. M. J. Org. Chem. 1987, 52, 1872-1874.
(17) ORTEP view of 6f.
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